Targeting glycogen synthase kinase-3 for oxidative stress and neuroinflammation: Opportunities, challenges and future directions for cerebral stroke management

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Cerebral stroke is a leading cause of early death and physical disability in adults throughout the world. Oxidative stress and inflammation plays an important role in the pathological process associated with the stroke. The available reperfusion therapy itself enhances the oxidative stress by overproduction of reactive oxygen species (ROS) and reactive nitrogen species (RNS) from the neurons, as well as non-neuronal cells, thus further worsens the condition. Excessive ROS and RNS production contributes to the brain injury during or after the stroke by activating inflammatory processes. Glycogen synthase kinase-3 (Gsk-3) is an evolutionary conserved serine-threonine kinase that plays an important role in cellular growth, development, inflammation and apoptosis processes. Gsk-3 is activated during the brain stroke and suppresses the expression of nuclear factor-E2-related factor 2, an important regulator of endogenous antioxidant defence mechanism. It also modulates the expression of anti-inflammatory protein like, cAMP response element binding protein and activator protein 1. It has been found that the inhibition of Gsk-3 shows neuroprotection via reducing the oxidative stress and inflammation in cerebral ischemia/reperfusion. The present review describes in depth the role of oxidative stress, neuroinflammatory processes and endogenous defence systems involved in cerebral stroke pathogenesis, and their regulation by Gsk-3. Further the reports of all the potential agents modulating Gsk-3 activity via different signalling pathways have been summarized to substantiate its effectiveness in cerebral stroke management.HIGHLIGHTSGsk-3 plays an integral role in cerebral stroke pathogenesis.Oxidative stress during ischemia modulates the Gsk-3 activity.Nrf2 expression is altered following Gsk-3 activation.Activated Gsk-3 enhances neuro inflammatory processes.Gsk-3 inhibition can be a potential therapy for management of cerebral stroke.

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